ࡱ> 5@bjbj22PXX@ttttttt$---P-,.._h//(8/8/8/000^^^^^^^`Rb^9t50055^tt8/8/^HHH5t8/t8/^H5^HHIeXtt=Z8// ȳ N-D&1YyZ4^0._KYcGc4=Zttttct=Z<0Vi1H]2!3000^^(-H- MULTIPLE PRIMARY INTRATHORACIC NEOPLASMS: CASE REPORT AND A REVIEW OF THE LITERATURE Tatjana Peroa-Golubi i, Silvana Smojver-Je~ek, Marijan Gore an, Njeto ka Gredelj,, Jasna Tekavec-Trkanjec, Marija Alilovi, Doc dr. sc. Tatjana Peroa-Golubi i University Clinic for Lung Diseases 10 000 Zagreb, Jordanovac 104, CROATIA Tel. + 385 1 23 85 142, Fax. + 385 1 23 48 345 E-mail : tatjana.peros-golubicic@zg.htnet.hr KEY WORDS: Intrathoracic, multiple neoplasms ABSTRACT Multiple neoplasms in a single patient, synchronous or metasynchronous is not a rare event, the incidence varies from 1% to 11% of all the neoplasms. They can be hereditary, connected with some environmental agents or previous therapies. The incidence of multiple neoplasms rises with age. We report an extremely rare case of multiple intrathoracic neoplasms (mesothelioma, carcinoid and B-cell lymphoma) in a 71-year old man previously treated for cutaneous T-cell lymphoma. The left upper lobectomy was performed and was followed by 6 courses of chemotherapy and the irradiation of the sternum. He was stable two years later. KEY WORDS: Intrathoracic, multiple neoplasms INTRODUCTION Multiple primary neoplasms in a single patient have been reported as early as the end of the 19th century (1), and since then numerous works concerning the etiopathogenesis, diagnosis and prognosis of such cases have been performed. The pathologic criteria of multiple neoplasms was summarised by Warren and Gates (2); tumors are considered to be arising independently if they exhibit different histology characteristics indicative of a subtype or degree of differentiation, if they are located in different lobes and are not accompanied by tumors of other organs. Molecular markers including the pattern of DNA ploidy, chromosome 3 p depletion, K-ras and p53 mutational pattern also have been used to identify the independent origin of multiple tumors (3). Multiple neoplasms could be defined, concerning their appearance in time, as synchronous or metasynchronous; the latter are defined as second and metasynchronous if they appear 6 months or latter following the first neoplasm (4). Etiopathogenesis of multiple neoplasms (5) includes hereditary aspects (familial occurrence with increased incidence, but also the influence of the protective factors) (6,7). It also includes the influence of external factors (tobacco, combined effects of tobacco and alcohol, asbestos, nutritional factors, viruses, the loss of immunity) (8,9,10) and the effects of previous therapies (especially with cytotoxic agents and hormones, immunosuppressants and irradiation) (11,12) or influance of tumour producing hormons (secretin, gastrin, bombesin, cholecystokinin, vasoactive intestinal peptide)(13)(Table 1.). From review of the recent literature it would appear that incidence of multiple neoplasms rises with age (14). CASE REPORT A 71-year old man was admitted to the hospital with a month history of chest pain, dry cough, dispnoa and malasia. Five years before he was treated for biopsy proven mycosis fungoides with etretinate for six months with a considerable success. The chest auscultation showed diminished breath sounds in the left lung. Routine laboratory findings were normal except for sedimentation rate of 130. The chest radiograms showed hyperinflation of the parenchyma in the supradiaphragmal and retrosternal region, a pathological process of the anterior upper mediastinum, an infiltration of the peripheral lingula 3 cm in the diameter and smaller one in the apicoposterior subsegment of the left upper lobus (Fig.1.a, 1.b.). Fiberbronhoscopy showed a tumor with smooth surface in the subsegmental bronchus of the left upper lung lobe. Bronchial brushing cytology (Fig.2.a.) and pathohistological analyses of the tumor biopsy proved that the tumor was carcinoid. The transthoracic fine needle aspiration of mediastinal mass did not reveal its aetiology. The patient underwent an operation, left upper lobectomy and mediastinal biopsy were performed. During the operation the node in the lingula was seen fixed to the pericardium. The intraoperative imprint cytology of the infiltrate in the lingula and pericardium revealed a malignant tumor. The tumor was firm, grey-white, 2.5x2 cm in size, composed of pleomorphic atypical epithelial cells in tubulopapilary formations and desmoplastic stroma (Fig.2.b.). The immunohistochemistry showed NSE and BerEP4 negative, EMA and cytokeratin positive tumor cells. Pathohistological diagnosis was a malignant mesothelioma. A similar infiltrate was found in the upper lobus of the left lung, 0.4x4 cm in size. In the apicoposterior subsegmental bronchus of the left upper lobe a sharply demarcated, smooth, soft, fleshy tumor was found, 0.8 cm in diameter, composed of uniform cells with eosinophilic cytoplasms in acinar formations, NSE and cytokeratin positive, EMA negative. The diagnosis was typical carcinoid. The mediastinal tumor was white, homogenous, 4 x 2 x 0,6 cm in size, composed of atypical small lymphoid cells lymphoplasmocytoid type, B immunophenotype. The conclusion was non-Hodgkin lymphoma of lymphoplasmocytoid type/ immunocytoma. In two of the synchronous tumors immunocytoma and mesothelioma, overexpression of the p53 tumor suppressor gene product was found. During the postoperative period a painful tumor of the sternum arose. The chest CT showed mediastinal mass with ventral, thoracic border, which was not sharp but irregular, suggesting the infiltrative growth. (Fig.1.c.) The fine needle aspiration showed the cells of non-Hodgkin lymphoma. (Fig.2.c.) The patient underwent six courses of chemotherapy (protocol CHOP: adriamycin, ciclophosphamide, oncovin and metilprednisolon) and the irradiation of the sternum. Two years later the patient was without symptoms, conventional chest radiogram and CT scan showed only a fibrous residue and there were no signs of local or distant spreading of any of the tumors. DISCUSSION This is a case of multiple intrathoracic neoplasms: mesothelioma, carcinoid and B-cell lymphoma, in a patient who has been treated for cutaneous T-cell lymphoma. Similar case has not been reported previously. Multiple primary neoplasms in a single individual are extremely rare when more then three distinct lesions are considered (15). The incidence of multiple primary lung cancer ranges from 0,5% to 10% (16). In clinical reports patients with multiple primary cancer of upper aerodigestive tract have been described (17,18), as well as combination of other malignant neoplasms and patients with multiple primary lung cancer. (10,13,16,17,19,20,22,30,31). (Table 2.) It would appear that patients who have developed one neoplasm of aerodigestive tract might be at greater risk of developing a second primary tumor, particularly with alcohol consumption and smoking habits. when they used alcohol and are heavy smokers. In the case of lung cancer the occurrence of a metachronous primary lung tumors has been over 10% for patients surviving more then 3 years. Criteria of multiple lung neoplasms modified from Martini and Melamed (21) include demonstration of tumors with different histology and proof that tumors, if histologically similar, arise from separate and distinct endobronchial foci. Many authors exclude cases in which there is more than one tumor of given histological type, arguing that the second tumor cannot be distinguished from intrapulmonary metastasis (22). We reported patient with three intrathoracal malignant tumors from different origins. Our patient had carcinoid, tumor from neuroendocrine origin, mesothelioma, malignant mesenchymal tumor, intrathoracic B-cell lymphoma and cutaneous T-cell lymphoma. Etretinate is a monoaromatic retinoid used in the treatment of keratinising skin disorders and cutaneous T-cell non-Hodgkin lymphomas (23). Teratogenic potential has been described, as well as the induction of different skeletal alterations, even the perosteal osteosarcoma (24). Etretinate has been administered to our patients for 6 months, five years before diagnosis of multiple second malignancies and we cannot affirm the connection between those events. No specific hereditary syndrome could be identified from the patient's pedigree or the environmental causative agents responsible for the development of multiple malignancies. Individuals with history of multiple neoplasms should have a complete family history evaluation and follow-up for development of subsequent primary neoplasms. Several studies have shown increased risk of multiple neoplasms for older patients, especially for those earlier treated with aggressive anticancer drugs. The percent of patients older than 50 years who developed multiple neoplasms varies from 71% to 94% in different series (25-29). The reason for increased incidence of multiple neoplasms could be generally older population, and on the other hand more effective antitumorous therapy that prolongs patients lives and increases risk for other primary neoplasms. Our patient, as reported, has been treated efficiently for another malignancy. TABLE 2. REPORTS OF MULTIPLE MALIGNANT NEOPLASMS AuthorsRefPrimary neoplasmSecond primary neoplasmsMultiple primary neoplasmsTondini10//Mesothelioma, NHL- BcellHabal13Colon adenocarcinomaCarcinoid/Demandante14//Ureteral/bladder/urethral transitional cell carcinoma, prostatic adenocarcinomaAntakli16Lung cancerLung cancer second primary/Keshishian17Tonsillar squamous carcinomaLung adenocarcinoma Esophagus and tongue squamous carcinoma/Gerstle19Gastrointestinal carcinoidMalignant neoplasms of gastrointestinal or other localisations/Takabe20MesotheliomaNHL B cell/ TABLE 2. (nova) REPORTS OF MULTIPLE PRIMARY MALIGNANT NEOPLASMS AuthorsRefMultiple primary neoplasmsNo. of patientsYearCarey22Lung cancers191993.Ferguson30Lung cancers1171993.Tondini10Mesothelioma NHL- B cellCase report1994.Antakli16Lung cancers541995.Gerstle19Gastrointestinal carcinoid Malignant neoplasms of gastrointestinal or other localisations321995.Takabe20Mesothelioma NHL B cellCase report1997.Keshishian17Tonsillar squamous carcinoma Lung adenocarcinoma Esophagus and tongue squamous carcinomaCase report1998.Habal13Colon adenocarcinoma CarcinoidCase report2000.Beshay31Pulmonary typical carcinoidsCase report2003. TABLE 1. SOME ETIOPATHOGENETIC FACTORS OF MULTIPLE PRIMARY NEOPLASMS IN A SINGLE PATIENT (5) Mechanisms of carcinogenesis _____________________________________________________________ Chemical Tobacco Lungs, upper respiratory tract Tobacco+alcohol Larynx, lungs, upper digestive tract Asbestos Mesothelioma, lungs Cadmium Prostate, kidneys, lungs Nickel Lungs, parnasal sinuses Arsenic Skin, lungs Nutritional and/or endocrine Breasts, corpus uteri, ovaries, colon Viral Burkitt's lymphoma, non-Hodgkin lymphoma Immunodefficiency Thymoma, skin cancer, non-Hodgkin lymphoma Following the therapy for Hodgkin's disease, lymphomas and Kaposi sarcomas in AIDS _____________________________________________________________ REFERENCES Billroth T. Die Allgemeine Chirurgische Pathologie and Therapie. In: Reimer G. Vorlesungen-Ein Handbuch fur Studierende and Artze, 14, Berlin:Auflage, 1889. Waren S, Gates O. Multiple primary malignant tumors: a survey of literature and statistical study. 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Synchronous primary lung cancers: prevalence in surgical material and clinical implications. Thorax 1993; 48:344-346. Zachariae H, Thestrup-Pedesen K. Interferon alpha and etretinate combination treatment of cutaneous T-cell lymphoma. J Invest Dermatol 1990; 95:206-208. Vilon P, Fiche M, Maugars Y, et al. Parosteal sarcoma of radius in the course of etretinate therapy. Rev Rheum Mal Osteoartic 1991; 58:825-827. Hajdu SI, Hajdu EO. Multiple primary malignant tumors. J Am Geriatr Soc 1968; 16:16-26. Berge T, Cederqvist L, Schonebeck J. Multiple primary malignant tumors: an autopsy study of a circumscribed population. Acta Pathol Microbiol Scand 1969; 76:171-183. Haddow AJ, Boyd JF, Graham AC. Multiple primary neoplasms in the Western Hospital Region, Scotland: a survey based on cancer registration data. Scott Med J 1972; 17:143-152. Lee TK, Myers RT, Scharyj M. Multiple primary malignant tumours (MPMT): study of 68 autopsy cases (1963-1980). J Am Gerietr Soc 1982; 30:744-753. 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